Total synthesis of nahuoic acid A via a putative biogenetic intramolecular Diels–Alder (IMDA) reaction. Issue 45 (15th November 2021)

• Record Type: Journal Article
• Authors: Guillade, Lucía; Mora, Paula; Villar, Pedro; Alvarez, Rosana; R. de Lera, Angel
• Is Part Of: Chemical science. Volume 12:Issue 45(2021)
• Page Start: 15157
• Page End: 15169
• Publication Date: 2021-11-15
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc04524e
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : The total synthesis of natural product nahuoic acid A, a cofactor-competitive inhibitor of the epigenetic enzyme lysine methyl transferase SETD8, has been carried out based on the biogenetic proposal of an intramolecular Diels–Alder (IMDA) cycloaddition. Abstract : Inspired by the biogenetic proposal of an intramolecular Diels–Alder (IMDA) cycloaddition, the total synthesis of natural product nahuoic acid A, a cofactor-competitive inhibitor of the epigenetic enzyme lysine methyl transferase SETD8, has been carried out. A non-conjugated pentaenal precursor was synthesized with high levels of stereoselectivity at seven stereogenic centers and with the appropriate control of double bond geometries. Although the IMDA reaction of the non-conjugated pentaenal using Me2 AlCl for catalysis at −40 °C selectively afforded the trans -fused diastereomer corresponding to the Re-endo mode of cycloaddition, under thermal reaction conditions it gave rise to a mixture of diastereomers, that preferentially formed through the exo mode, including the cis -fused angularly-methylated octahydronaphthalene diastereomer precursor of nahuoic acid A. The natural product could be obtained upon oxidation and overall deprotection of the hydroxyl groups present in the Si-exo IMDA diastereomer.